The invention relates to compounds which are useful as anti-endotoxic drugs, particularly analogs of lipid A.
The incidence of gram negative bacteremia in the United States has been estimated to be approximately 100,000 to 300,000 cases per year, with a mortality rate of 30-60% (Dudley, Am. J. Hosp. Pharm. 47, Supp.3:S3, 1990). Antibiotics are commonly used as the primary chemotherapy for this disease; however, their bactericidal action results in disruption of the bacterium and concomitant release of endotoxin, i.e., the lipopolysaccharide (LPS) moiety of the bacterial outer membrane. The liberated LPS induces a number of pathophysiological events in mammals (collectively referred to as gram-negative endotoxemia or sepsis syndrome): these include fever, generalized inflammation, disseminated intravascular coagulation (DIC), hypotension, acute renal failure, acute respiratory distress syndrome (ARDS), hepatocellular destruction, and cardiac failure (Dudley, supra; Braunwald et al., eds., Harrison's Principles of Internal Medicine, 11th ed., McGraw-Hill Book Co., New York, 1987).
Although the endotoxin initiates sepsis, it has little or no direct effect on tissues; instead, it triggers a cascade of biologic mediators which lead to sepsis and septic shock. Endotoxin stimulates monocytes and macrophages to produce tumor-necrosis factor and interleukin-1, two major primary mediators. These mediators then cause the sepsis syndrome by stimulating inflammatory or other cells, such as endothelial cells, to secrete a cascade of secondary mediators (e.g., prostaglandins, leukotrienes, interferons, platelet-activating factor, endorphins, and colony-stimulating factors). These inflammatory mediators influence vasomotor tone, microvascular permeability, and the aggregation of leukocytes and platelets. Although the actions and interactions of these substances appear to be complex, their net effect in initiating septic shock appears to be very significant (Braunwald et al., supra).
As reported by DiPiro (Am. J. Hosp. Pharm. 47, Supp.3:S6, 1990), the bacterial lipopolysaccharide molecule has three main regions: a long-chain polysaccharide (O Antigen) region, a core region, and a lipid A region. The entire lipopolysaccharide molecule and some of its components have toxic effects. Most of these toxic effects, however, are believed to be attributable to the lipid A portion. Structurally, lipid A is composed of a disaccharide and acylated by long-chain fatty acids.
Therapies for endotoxin-related diseases have generally been directed toward controlling the inflammatory response. Such therapies include: corticosteroid treatment, suggested to ameliorate endotoxin-mediated cell membrane injury and to reduce production of certain biologic mediators (Bone,N, Eng. J. Med. 317:653, 1987; Veterans Administration Systemic Sepsis Cooperative Study Group, N. Eng. J. Med. 317:659, 1987; Braunwald et al., supra); administration of antibodies designed to neutralize the bacterial LPS endotoxin (see, e.g., Ziegler et al., N. Eng. J. Med. 307:1225, 1982); treatment with naloxone, which apparently blocks the hypotensive effects associated with the sepsis syndrome (Sheagren et al., Shock Syndromes Related to Sepsis. In: Wyngaarden and Smith, eds., Cecil Testbook of Medicine, 18th ed. Philadelphia, 1988, pp 1538-41); and treatment with nonsteroidal anti-inflammatory drugs, purported to block cyclo-oxygenases and thereby decrease the production of certain secondary mediators such as prostaglandins and thromboxane (DiPiro, supra).